VTPA 342 Inflammation
Terms
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- Inflammation is
-
the reaction of vascularized living tissues to
`` local injury which
`` comprises a series of
`` changes in
`` `` the terminal vascular bed,
`` `` in the blood, and
`` `` in the connective tissues
`` that are designed to
`` `` eliminate the offending irritant and
`` to repair the damaged tissue - The inflammatory response is a complex and highly ordered sequence of events that
-
serves to
`` concentrate the body’s
`` `` humoral and
`` `` cellular
`` defenses at the site of
`` `` injury or
`` `` infection,
`` avoiding wasteful dilution of these resources
`` and also minimizing the risk of
`` `` unintentional injury to healthy tissues. - “cardinal signs†of inflammation:
-
calor (warmth),
dolor (pain),
tumor (swelling)
and rubor (redness and hyperaemia)
Rudolf Virchow (1821 – 1902) added the fifth “cardinal sign†of inflammation;
`` namely, functio laesa
`` `` (inhibited or lost function) -
Inflammation
Severity 4 -
Minimal –
`` negligible gross changes
`` often visible only histologically
Mild –
`` low degree of hyperemia and edema
`` with little or no
`` `` exudation and
`` `` tissue destruction.
Moderate –
`` obvious signs of inflammation
`` `` vascular and
`` `` cellular
`` with tissue destruction
`` usually
`` `` not life-threatening and
`` `` not compromising significantly organ function
Severe –
`` considerable tissue damage is present
`` with abundant exudation
`` usually
`` `` life-threatening or
`` `` compromising significantly organ function -
Inflammation
Duration 5 -
Peracute
Acute
Subacute
Chronic
Chronic Active -
Inflammation
Peracute inflammation is -
manifested a
`` few hours after its initiation
it is usually caused by a potent stimulus
Gross:
`` ``edema,
`` `` hyperemia, and/ or
`` `` hemorrhage
`` `` `` only a few leucocytes without exudation
Example:
`` anaphylaxis -
Inflammation
Acute inflammation begins -
within
`` `` 4-6 hours after stimulus
`` and lasts
`` `` 3-4 days
Gross:
`` rubor,
`` `` hyperemic,
`` calor,
`` `` warm,
`` tumor,
`` `` swollen,
`` dolor
`` `` painful);
`` hemorrhage,
`` exudation of
`` `` fibrin and
`` `` neutrophils
Examples:
`` Fibrinous bronchopneumonia,
`` Parvoviral enteritis -
Inflammation
Subacute inflammation is characterized by -
gradual decline in vascular contribution
`` `` edema and
`` `` hyperemia
`` and mixed cellular infiltrate
`` `` neutrophilic and
`` `` mononuclear
`` `` `` lymphocytes,
`` `` `` macrophages,
`` `` `` plasma cells
Example:
`` Prolonged fibrinous bronchopneumonia -
Inflammation
Chronic inflammation is usually -
caused by a persistent stimulus that
`` the host cannot get rid of
Ongoing inflammatory process consisting of
`` `` macrophages
`` `` `` (innate immunity)
`` `` and lymphocytes
`` `` and plasma cells
`` `` `` (acquired immunity)
Tissue reparative process:
`` angiogenesis
`` `` angioblast proliferation and
`` `` vascularization,
`` fibroplasia
`` `` fibroblast proliferation and
`` `` fibrosis
FIBROSIS (scarring) is
`` the most reliable indicator of chronicity.
Examples:
`` tuberculosis,
`` foreign body reaction,
`` abscess -
Inflammation
Chronic-active inflammation is characterized by -
both
`` chronic inflammatory characteristics
`` `` mononuclear inflammation and
`` `` fibrosis
`` and acute characteristics
`` `` neutrophilic and
`` `` fibrinous exudation
Examples:
`` Chronic-active pyoderma
`` `` bacterial suppurative inflammation of skin;
`` Chronic active fibrionus pericarditis
`` `` hardware disease - Serous exudate
-
`` Transparent,
`` yellow,
`` uncoagulated,
`` thin fluid (
`` `` exudate
usually on
`` `` serosal surfaces
`` derived either from
`` `` plasma
`` or less likely from
`` `` secretions of mesothelial cells lining the serosa
Serous exudate is called also
`` serous effusion
Examples:
`` Serous pericarditis,
`` Serous exudate in skin blister
`` `` resulting from a burn - Fibrinous exudate
-
With more severe endothelial injuries that
`` result in greater vascular permeability,
`` larger molecules such as
`` `` fibrinogen
`` pass the vascular barrier,
`` and fibrin is
`` `` formed and
`` `` deposited
`` in the
`` `` extracellular space or
`` `` body cavities -
Fibrinous exudate
Morphology:
Gross: 5 -
Serosal surface:
`` Small amount:
`` `` ground-glass appearance on
`` `` `` hyperemic serosa
`` `` `` `` (e.g. parvoviral enteritis)
`` Large amount
`` `` yellow,
`` `` soft,
`` `` elastic,
`` `` friable material
`` (e.g. fibrinous pleuritis)
Lungs:
`` yellow-red
`` `` interlobular and
`` `` intraalveolar
`` exudate that is in-part responsible for
`` `` consolidation of pulmonary tissue in
`` `` `` fibrinous bronchopneumonias
`` (e.g. shipping fever in Bo
Mucosal surfaces:
`` granular membrane consisting of
`` `` fibrin and
`` `` sloughed necrotic epithelium,
`` usually attached to underlying eroded/ulcerated mucosa
`` `` (diphtheritic membrane)
Joint:
`` white-yellow
`` friable material
`` floating within synovial fluid
Anterior ocular chamber:
`` floating white flakes -
Fibrinous exudate
o Microscopic: -
eosinophilic
`` meshwork of threads
`` or
`` `` amorphous,
`` `` homogeneous
`` coagulum -
Fibrinous exudate
Outcome: 2 -
Fibrinous exudates may be
`` removed by fibrinolysis
`` and clearing by macrophages
`` This process of resolution may
`` `` restore normal tissue structure
When the fibrin is not removed,
`` it may stimulate the
`` `` ingrowth of
`` `` fibroblasts and
`` `` blood vessels
`` and thus lead to
`` `` organization process resulting in
`` `` `` fibrosis and
`` `` `` scarring - Aging of serosal fibrinous exudate:
-
If fibrinous membranes peel off easily from the serosal surfaces,
`` then the fibrin has been there
`` `` less than ~ 4 days
`` `` (acute inflammatory process)
If fibrinous membranes are attached to the serosa and are difficult to peel off,
`` then organization process of fibrin
`` `` has begun and it is
`` `` older than ~ 4 days
`` `` subacute-chronic inflammation, or
`` `` chronic-active
Note - do NOT peel fibrinous mucosal exudate
`` rinse off luminal contents only
`` tf do not describe as friable -
Fibinous Exudate
Examples 6 -
Fibrinous polyserositis
`` Po: Glasser’s disease
`` `` Haemophilus parasuis
Fibrinous bronchopneumonia
`` Bo: Shipping fever –
`` `` Manheimia haemolytica
Fibrinous pericarditis
`` Bo: hardware disease
Fibrinous enteritis/enterocolitis
`` All spp:
`` `` Salmonellosis;
`` Bo:
`` `` Coccidiosis
Feline infectious peritonitis
`` FIP virus
Fibrinous erosive tracheitis
`` Bo: Infectious bovine rhinotracheitis
`` `` (IBR) virus - If fibrinous exudate is mixed/infiltrated by many neutrophils, it is
-
called
`` `` fibrinopurulent or
`` `` fibrinosuppurative
`` exudate - Suppurative or purulent exudate
-
Suppurative or purulent inflammation is characterized by
`` the production of large amounts of
`` `` pus or
`` `` purulent exudate
`` consisting of
`` `` neutrophils,
`` `` necrotic cells, and
`` `` edema fluid
Certain bacteria
`` `` (e.g. Arcanobacterium pyogenes)
`` produce this localized suppuration and
`` are therefore referred to as
`` `` pyogenic (pus-producing) bacteria -
Suppurative or purulent exudate
Morphology
Gross 3 -
within tissue or cavity
`` Opaque,
`` thick,
`` creamy fluid
`` `` pus
Unlike fibrinous exudate,
`` it is extremely difficult to determine
`` `` duration of suppurative exudate
`` `` unless it is accompanied by
`` `` `` fibrosis in which case
`` `` `` `` it is chronic
Pus is liquid;
`` therefore, it tends to
`` `` settle by gravity within cavities
`` Accordingly, in suppurative meningitis,
`` `` it will be more abundant in the
`` `` ventral portions of the meninges
`` `` `` along brain stem
`` `` then in dorsal portions of cerebrum -
Suppurative or purulent exudate
Morphology
Microscopic -
homogeneous,
`` disintegrated and
`` liquefied necrotic tissue
`` and neutrophils -
Suppurative or purulent exudate
Diagnostic significance: 2 -
Presence of neutrophils indicates
`` that lesion is
`` `` acute or
`` `` chronic-active
It is predominantly caused
`` by bacteria - Abscess is
-
localized accumulation of pus
`` surrounded by fibrous wall
`` `` (capsule)
Pus usually contains
`` `` bacteria
`` which are stimulus for
`` `` continuous migration of
`` `` ` neutrophils
The fibrous wall
`` `` isolates and
`` `` prevents
`` this infectious process from spreading
Ideally,
`` neutrophils
`` `` gain control over infection,
`` `` kill bacteria and
`` `` together with macrophages
`` `` `` clean debris
Capsule in this case becomes
`` thicker and thicker until
`` `` `` the entire abscess is organized by
`` `` `` `` ingrowth of
`` `` `` `` `` angioblasts and
`` `` `` `` `` fibroblasts
However, some bacteria (
`` `` e.g. Corynebacterium pseudotuberculosis)
`` are
`` `` resilient and
`` `` not easily killed
`` by neutrophils
Consequently,
`` a large amount of pus surrounded by
`` `` thin capsule represents
`` `` `` an abscess in which
`` `` `` `` body defenses are barely able to cope with
`` `` `` `` `` infection and
`` `` `` `` `` isolation
``Caseous lymphadenitis of sheep
`` `` with onion-like abscess appearance
`` is a good example
The abscess “onion-rings†represent
`` previous fibrous capsules that were
`` `` overwhelmed by the spreading suppuration,
`` with a new capsule forming around the ever-enlarging abscess - Hemorrhagic inflammation –
-
usually peracute inflammation with
`` vascular necrosis - Mucoid = catarrhal inflammation –
-
on mucus membranes
`` (e.g. nasal cavity) - Non-suppurative inflammation –
-
mononuclear
`` lymphocytes,
`` plasma cells,
`` macrophages
inflammatory infiltration
(e.g. viral infection in the CNS) - Granulomatous inflammation is
-
a distinctive pattern of
`` chronic inflammatory reaction
`` characterized by focal accumulations of
`` `` activated macrophages,
`` `` `` which often develop an epithelioid appearance - A granuloma is
-
a focus of chronic inflammation consisting of
`` a aggregation of
`` `` epithelioid macrophages
`` `` `` often with giant cells
`` `` surrounded by
`` `` `` lymphocytes,
`` `` `` occasionally plasma cells and
`` `` `` fibroblasts.
Examples:
`` `` Mycobacterial,
`` `` fungal,
`` `` foreign body
`` granulomas -
Inflammation
Morphologic diagnosis -
It is interpretive summary of
`` `` the gross or
`` `` microscopic
`` description of pathological changes which
`` `` must indicate
`` `` `` location and
`` `` `` process
`` ``together with a few most useful adjectives
`` `` `` severity,
`` `` `` duration,
`` `` `` distribution,
`` `` `` type of exudate,
`` `` `` and/or other modifier -
Inflammation
Morphologic diagnosis
Severity 4 -
Minimal
Mild
Moderate
Severe -
Inflammation
Morphologic diagnosis
Duration 5 -
Peracute
Acute
Subacute
Chronic
Chronic-active -
Inflammation
Morphologic diagnosis
Distribution 6 -
Focal
Multifocal
Locally extensive
Diffuse
Bilateral
Zonal -
Inflammation
Morphologic diagnosis
Exudate 6 -
Serous
Fibrinous
Purulent
Granulomatous
Caseous
Non-suppurative -
Inflammation
Morphologic diagnosis
Other 6 -
Erosive
Ulcerative
Necrotizing
Proliferative
Fibrous
Anat. location -
Inflammation
Morphologic diagnosis
itis -
When process is inflammation
Dont Forget it !!!!!!!!!
ie Hepatiits - ACUTE INFLAMMATION
-
The vascular and cellular inflammatory reactions are
`` mediated by
`` `` chemical mediators that are derived from
`` `` `` plasma proteins or
`` `` `` cells
`` `` in response to the inflammatory stimulus - Stimuli for acute inflammation: 6
-
Infections
`` `` bacterial,
`` `` viral,
`` `` parasitic
`` and microbial toxins
Trauma
`` `` blunt and
`` `` penetrating
Physical and chemical agents
`` thermal injury,
`` `` burns or
`` `` frostbite;
`` `` irradiation;
`` `` environmental chemicals
Tissue necrosis
`` `` from any cause
Foreign bodies
`` `` splinters,
`` `` dirt,
`` `` sutures
Immune reactions
`` also called hypersensitivity reactions
Each of these stimuli may induce
`` reactions with some distinctive features,
`` but all inflammatory reactions
`` `` share the same basic features -
Inflammation
VASCULAR CHANGES -
Normally,
`` `` plasma proteins and
`` `` circulating cells
`` are sequestered inside
`` `` the vessels
`` and move in the direction of flow
In inflammation,
`` blood vessels undergo a series of changes that are
`` designed to maximize the movement of
`` `` plasma proteins and
`` `` circulating cells
`` out of the circulation and
`` into the site of injury or infection -
Changes in blood flow and vascular caliber and permeability
The vascular changes occur in the following order : -
Vasodilation induced by
`` `` histamine,
`` `` prostaglandins and
`` `` nitric oxide:
`` `` `` arteriolar dilatation
`` increased blood volume
`` `` opening of new capillary beds in the area
`` `` `` hyperemia
`` `` `` ↑ heat and
`` `` `` ↑ redness
Increased permeability of the microvasculature
`` induced by
`` `` histamine,
`` `` bradykinin,
`` `` leukotrienes,
`` `` anaphylatoxins
`` `` `` C3a and
`` `` `` C5a
`` `` cytokines]
`` outpouring of protein-rich fluid into
`` `` the extravascular tissues
The loss of fluid results in
`` concentration of cellular fraction of blood
`` `` in capillaries and
`` `` venules,
`` increased viscosity of the blood,
`` and slower blood flow
`` `` (stasis)
Neutrophils accumulate along the vascular endothelium,
`` stick to the endothelium,
`` and soon afterward
`` `` migrate through the vascular wall into
`` `` `` the interstitial tissue - A hallmark of acute inflammation is
-
increased vascular permeability
`` leading to the escape of a protein-rich fluid
`` `` `` (exudate)
`` `` into the extravascular tissue
The loss of proteins from the plasma
`` `` due to increased endothelial leakage
`` reduces the intravascular osmotic pressure
`` and increases the osmotic pressure of the interstitial fluid
Together with the increased hydrostatic pressure
`` `` owing to increased blood flow through the dilated vessels,
`` this leads to a marked outflow of fluid
`` and its accumulation in the interstitial tissue
The net increase of extravascular fluid results in
`` `` edema - Mechanisms of increased endothelial leakage 5
-
Immediate and Transient Leakage
Delayed Leakage
Immediate and Sustained Leakage
Leukocyte Mediated Endothelial injury
Leakage from new Blood Vessels - Immediate and transient leakage is
-
caused by formation of endothelial gaps
`` induced by
`` `` histamine,
`` `` bradykinin,
`` `` leukotrienes
It occurs rapidly after
`` exposure to the mediator
`` and is usually reversible
`` and short-lived
`` `` (15 to 30 minutes)
Mediators initiate
`` contraction of cytoskeletal proteins
`` `` (myosin)
`` leading to contraction of the
`` `` endothelial cells and
`` `` formation of intercellular gaps - Delayed leakage is
-
caused by formation of endothelial
`` gaps induced by
`` `` cytokines
`` `` `` interleukin-1 (IL-1),
`` `` `` tumor necrosis factor (TNF),
`` `` and interferon-γ (IFN-γ)
In contrast to the histamine effect,
`` the cytokine-induced response is
`` `` somewhat delayed
`` `` ` (4 hours)
`` `` and long-lived
`` `` `` (12 - 24 hours)
Similar to the histamine effect,
`` cytokines induce increase vascular permeability by
`` `` structural reorganization of the cytoskeleton,
`` `` `` such that the endothelial cells retract from one another
`` `` `` and form intercellular gaps - Immediate and sustained leakage is
-
caused by
`` direct endothelial injury,
`` resulting in endothelial cell
`` `` necrosis and
`` `` detachment
This effect is usually encountered in
`` `` necrotizing injuries
`` and is due to
`` `` direct damage to the endothelium
`` `` by the injurious stimulus
`` `` `` burns,
`` `` `` bacterial toxins
In most instances,
`` leakage starts
`` `` immediately after injury
`` and is sustained at a high level for
`` `` several hours
`` until the damaged vessels are
`` `` thrombosed or
`` `` repaired - Leukocyte-mediated endothelial injury.
-
Activated leukocytes
`` adhere to endothelium
`` `` relatively early in inflammation
They may release
`` `` toxic oxygen species
`` `` and proteolytic enzymes,
`` which then may cause
`` `` endothelial injury or
`` `` detachment - Leakage from new blood vessels
-
during repair, endothelial cells
`` `` angioblasts
`` proliferate
`` and form new blood vessels,
`` `` a process called angiogenesis
New vessel sprouts
`` remain leaky until
`` `` the endothelial cells mature
`` `` and form intercellular junctions -
In summary,
in acute inflammation,
fluid loss from vessels with increased permeability
occurs in distinct phases: 3 -
an immediate transient response
`` lasting for
`` `` 30 minutes
`` mediated by
`` `` histamine,
`` `` bradykinin and
`` `` leukotrienes
a delayed response
`` starting at about
`` `` 4 hours
`` and lasting for
`` `` 12-24 hours
`` mediated by
`` `` cytokines
a prolonged response that is
`` most noticeable after
`` `` direct endothelial injury by
`` `` `` toxins and
`` `` `` leukocytes -
Exudate
Charcteristics 6 -
Apperance
`` Turbid to opaque,
`` `` variable color
Etiology
`` Inflammation
Prtein Content
`` >30 g/L
Clottable
`` Sometimes
Necleated Cells
`` >1.5 x 109/L*
`` `` * >5-9 x 109 cells per liter are present before an exudate is suspected in horses
Bacteria
`` Sometimes -
Transudate
Charcteristics 6 -
Appearance
`` Clear or
`` lightly yellow
Etiology
`` Hemodynamic imbalance
Protein Content
`` <30 g/L
Clottable
`` Rarely
Nucleated Cells
`` <1.5 x 109/L
Bacteria
`` Almost never -
Inflammation
CELLULAR EVENTS
A critical function of inflammation is to -
activate and deliver leukocytes to the site of injury
Leukocytes
`` ingest offending agents,
`` kill microbes, and
`` get rid of
`` `` necrotic tissue and
`` `` foreign substances
A price that is paid for the defensive potency of leukocytes is
`` that they may
`` `` induce tissue damage and
`` `` prolong inflammation,
`` since the leukocyte products that destroy
`` `` microbes and
`` `` necrotic tissues
`` can also injure normal host tissues -
Exudate
Characterisitcs 6 -
Appearance
`` Turbid to opaque,
`` variable color
Etiology
`` Inflammation
Protein Content
`` >30 g/L
Clottable
`` Sometimes
Nectleated Cells
`` >1.5 x 109/L*
`` `` * >5-9 x 109 cells per liter are present before an exudate is suspected in horses
Bacteria
`` Sometimes -
Transudate
Characteristics 6 -
Apperarnce
`` Clear or
`` lightly yellow
Etiology
`` Hemodynamic imbalance
Protein Content
`` <30 g/L
Clottable
`` Rarely
Nucleated Cells
`` <1.5 x 109/L
Bacteria
`` Almost never -
Inflammation
CELLULAR EVENTS
A critical function of inflammation is -
to activate and deliver leukocytes to
`` the site of injury
Leukocytes
`` `` ingest offending agents,
`` `` kill microbes,
`` `` and get rid of
`` `` `` necrotic tissue and
`` `` `` foreign substances -
Inflammation
CELLULAR EVENTS
A price that is paid
for the defensive potency of leukocytes is -
that they may
`` `` induce tissue damage
`` `` and prolong inflammation,
`` since the leukocyte products that destroy
`` `` microbes and
`` `` necrotic tissues
`` can also injure normal host tissues - The sequence of leukocytic events can be divided into: 4
-
In the lumen:
`` margination,
`` rolling, and
`` adhesion to endothelium
Normal vascular endothelium
`` does not interact with
`` `` circulating blood cells
`` and prevents their extravasation
Activated endothelium permits
`` `` attachment and
`` `` exit of leukocytes
`` from the blood vessels
Transmigration across the endothelium
`` (also called diapedesis)
Migration in interstitial tissues
`` toward a chemotactic stimulus
`` `` (chemotaxis)
Phagocytosis
`` and synthesis of biochemical mediators -
Leukocyte Migration
6 Steps -
Margination
Rolling
Firm Adhesion
Diapedesis
Chemotaxis
Phagocytosis - Margination
-
Process of leukocyte accumulation
Venular blood flow slows early in
`` inflammation
`` `` (stasis)
and white cells assume
`` a peripheral position
`` along the endothelial surface - Rolling
-
individual and then rows
`` of leukocytes
`` tumble slowly along
`` the endothelium and
`` adhere
`` `` transiently - Firm Adherence
-
coming to rest at some point
`` along endothelium - Diapedesis begins:
-
leukocytes insert pseudopods into
`` the junctions between
`` `` the endothelial cells,
`` squeeze through interendothelial junctions,
`` and assume a position between
`` `` the endothelial cell and
`` `` the basement membrane - Chemotaxis
-
Chemotaxis is
`` directed movement of cells toward a chemical attractant
`` or leukocytic locomotion oriented along a chemical gradient
Both exogenous and endogenous substances can
`` act as chemoattractants
The most common exogenous agents are
`` bacterial products
`` `` peptide with N-formyl-methionine terminal amino acid or
`` `` lipids
Endogenous chemoattractants include several chemical mediators:
`` components of the complement system,
`` `` particularly C5a
`` products of the lipoxygenase pathway,
`` `` mainly leukotriene B4
`` cytokines,
`` `` particularly those of the chemokine family
`` `` `` IL-8,
`` `` `` MIP-1 - Phagocytosis
- to ingest and kill microbes –
- Neutrophils, monocytes, lymphocytes, eosinophils, and basophils all
-
use the same pathway to
`` migrate from the blood into tissues - Leukocyte adhesion and transmigration are regulated largely by
-
the binding of
`` complementary adhesion molecules
`` on the
`` `` leukocyte and
`` `` endothelial
`` surfaces
Chemical mediators
`` `` chemoattractants and
`` `` certain cytokines
`` affect these processes by
`` altering the
`` `` surface expression or
`` `` avidity of
`` such adhesion molecules -
The adhesion receptors
involved in
leukocyte adhesion and transmigration
belong to four molecular families: -
Selectins
Integrins
Immunoglobulins
Mucin like Glycoproteins - Selectins
-
are sugar-binding proteins
`` on endothelium
`` `` E-selectin,
`` `` P-selectin),
`` on platelets
`` `` P-selectin),
`` and on leukocytes
`` `` L-selectin
E- and P-selectins bind to
`` glycoproteins
`` `` sialylated forms of oligosaccharides -
`` `` `` sialylated Lewis X
`` on leukocytes and
`` `` mediate the rolling phase - Integrins
-
β1 and β2
are transmembrane heterodimeric glycoproteins
`` made up of
`` `` α and β chains,
`` that are
`` `` expressed on leukocytes and
`` `` bind to ligands
`` `` `` ICAM-1,
`` `` `` VCAM-1
`` on endothelial cells
`` `` firm adhesion - Immunoglobulin superfamily:
-
ICAM-1
`` `` intercellular adhesion molecule 1
`` and
VCAM-1
`` `` vascular cell adhesion molecule 1
`` on endothelium serve as
`` ligands for
`` `` integrins found on leukocytes - Mucin-like glycoproteins
-
(heparan sulfate)
contain a carbohydrate domain
`` `` (“sticky sugarâ€)
`` that serve as ligands for selectins
`` `` E,
`` `` P,
`` `` L - Endothelial molecules 5
-
P-selectin
`` rolling
E-selectin
`` rolling
ICAM-1
`` Firm adhesion
VCAM-1
`` Firm adhesion
CD31
`` leukocyte migration through endothelium - Leukocyte molecules 5
-
Glycoprotein (Sialyl-Lewis X)
`` rolling
Glycoprotein (Sialyl-Lewis X)
`` rolling
Integrins β2
`` firm adhesion
Integrins β1
`` firm adhesion
CD31
`` leukocyte migration through endothelium - Rolling of leukocytes: 2
-
Appearance of P- and E-selectins on endothelial surface:
`` Histamine and thrombin stimulate
`` the redistribution of
`` `` P-selectin from its normal
`` `` `` intracellular stores in granules
`` `` `` `` (Weibel-Palade bodies)
`` to the cell surface.
TNF and IL-1
`` `` (produced by activated leukocytes)
`` act on the endothelial cells
`` and within
`` `` 1 to 2 hours
`` E-selectin is expressed
Endothelial selectins bind carbohydrate ligands
`` expressed on leukocytes
This low-affinity binding is easily disrupted by
`` the flowing blood
As a result,
`` the bound leukocytes
`` `` detach and bind again,
`` and thus begin to roll along
`` `` the endothelial surface - Firm adhesion of leukocytes to endothelial cells
-
TNF and IL-1 also induce
`` endothelial expression of ligands for integrins,
`` `` mainly VCAM-1 and
`` `` ICAM-1
Leukocytes normally express these integrins in a
`` low-affinity state
Meanwhile, chemokines
`` `` that were produced at the site of injury
`` enter the blood vessel,
`` bind to endothelial cell membrane proteins
`` and are displayed at high concentrations on
`` `` the endothelial surface adjacent to the inflamed tissue
These chemokines activate the
`` rolling leukocytes
Consequently, integrins on the leukocytes are also
`` activated and they
`` `` firmly adhere to their ligands
`` `` VCAM-1 and
`` `` ICAM-1
`` on the endothelium
`` `` firm adhesion
The leukocytes stop rolling,
`` their cytoskeleton is reorganized,
`` and they spread out on the endothelial surface
`` `` (which is ‘paved by leukocytes’)
The type of inflammatory infiltrate
`` `` recruited to the sight of injury
`` depends on type of
`` `` chemokines attached to the endothelium
`` `` `` IL-8 will recruit neutrophils
`` `` `` macrophage inflammatory protein (MIP-1) attracts macrophages - Transmigration (emigration) or diapedesis of leukocytes through endothelium
-
Chemokines act on the
`` adherent leukocytes
`` and stimulate them to
`` `` migrate through interendothelial spaces
`` toward the chemical concentration gradient,
`` `` that is, toward the inflamed site
When neutrophils reach interendothelial cell junction,
`` CD31 adhesion molecules on neutrophils
`` `` recognize and bind to
`` `` `` their twins,
`` `` `` `` CD31,
`` `` on the endothelial cell junctions
This is “an exit signalâ€
`` and neutrophils
`` `` squeeze through endothelial cell junctions,
`` `` secrete proteinases
`` `` `` to get through the basement membrane
`` and crawl into the perivascular tissue
Once leukocytes enter the extravascular connective tissue,
`` they are able to adhere to the extracellular matrix by
`` `` β1 integrins
The type of emigrating leukocyte
`` varies with
`` `` the age of the inflammatory response and
`` `` with the type of stimulus
In most forms of acute inflammation,
`` neutrophils predominate in the inflammatory infiltrate during
`` `` the first 6 to 24 hours,
`` and then they are replaced by
`` `` monocytes in
`` `` `` 24 to 48 hours
Several reasons account for this sequence:
`` i) neutrophils are more numerous in the blood,
`` ii) they respond more rapidly to chemokines, and
`` iii) they may attach more firmly to the adhesion molecules that are
`` `` rapidly induced on endothelial cells
`` iv) after entering tissues,
`` `` neutrophils are short-lived;
`` `` `` they undergo apoptosis and disappear after
`` `` `` `` 24 to 48 hours,
`` v) monocytes survive longer
There are exceptions to this pattern of cellular exudation
In viral infections,
`` lymphocytes may be the first cells to arrive;
in some hypersensitivity reactions,
`` eosinophilic granulocytes may be the main cell type
These differences are determined by
`` inflammatory mediators
`` `` e.g. chemokines -
So, how does the leukocyte sense the chemotactic agents,
and
how do these substances induce directed cell movement? -
All the chemotactic agents mentioned above bind to specific receptors on the surface of leukocytes
Probably more receptors for chemokines are
`` occupied on one side of the cell,
`` `` (the side nearest to the inflamed tissue,)
`` providing a clue for the chemotactic direction
Signals initiated from these receptors result in
`` activation of several effectors that
`` ultimately increase
`` `` cytosolic calcium and
`` `` induce polymerization of actin-myosin filaments
`` `` `` (“tiny cellular musclesâ€)
`` `` at the leading edge of the cell
`` `` ` (closest to the inflamed area)
The leukocyte moves by
`` extending pseudopodia that
`` `` pull the back of the cell in
`` `` `` the direction of extension
Locomotion involves rapid assembly of
`` actin monomers into
`` linear polymers at the pseudopod's leading edge,
`` followed by disassembly of such filaments
`` `` away from the leading edge - Leukocyte activation
-
`` Microbes,
`` products of necrotic cells,
`` antigen-antibody complexes, and
`` cytokines,
`` `` including chemotactic factors,
`` induce a number of responses in
`` `` leukocytes
`` that are part of the defensive functions referred to
`` `` under the name of
`` `` `` leukocyte activation -
Leukocyte activation
Activation results from -
several signaling pathways that are
`` triggered in leukocytes,
`` `` resulting in increase in cytosolic calcium and
`` `` activation of enzymes such as
`` `` `` protein kinase C and
`` `` `` phospholipase A2 -
The functional responses that are induced on leukocyte activation
include the following: 4 -
Production of arachidonic acid metabolites
`` `` (eicosanoids)
`` from phospholipids,
`` as a result of activation of
`` `` phospholipase A2
`` by increased intracellular calcium
Degranulation and secretion of lysosomal enzymes
`` and activation of the oxidative burst
Secretion of cytokines,
`` which amplify and
`` `` regulate inflammatory reactions
``Activated macrophages are the
`` chief source of the cytokines that are
`` `` involved in inflammation
Modulation of leukocyte adhesion molecules
`` different cytokines cause
`` `` increased endothelial expression of adhesion molecules
`` `` and increased avidity of leukocyte integrins,
`` allowing firm adhesion of activated neutrophils to
`` `` endothelium - Phagocytosis and the release of enzymes by neutrophils and macrophages are responsible for
- eliminating the injurious agents
- Phagocytosis involves three distinct but interrelated steps:
-
recognition and binding of the particle to be ingested by the leukocyte
its engulfment,
`` with subsequent formation of a phagosome
killing or degradation of the ingested material -
Phagocytosis
Recognition and binding -
Typically the phagocytosis of
`` `` microbes and
`` ``dead cells
``is initiated by
`` `` recognition of the particles by
`` `` receptors expressed on the leukocyte surface -
Phagocytosis
Recognition and binding
Mannose receptors and scavenger receptors are -
two important receptors that
`` `` bind microbes
`` which are subsequently ingested by macrophages
The mannose receptor is a macrophage lectin that binds
`` `` terminal mannose and
`` `` fucose residues of
`` glycoproteins and glycolipids expressed only
`` `` on microbial cell walls
`` `` and not on the host cells -
Phagocytosis
Recognition and binding
The efficiency of phagocytosis is -
greatly enhanced
`` when microbes are
`` `` opsonized by
`` `` `` specific proteins
`` `` `` `` (opsonins)
`` `` for which the phagocytes express
`` `` `` high-affinity receptors - Opsonin
-
protein that binds to
`` antigens and
`` enhances their phagocytosis - opsonization,
-
The process of coating a particle,
`` `` such as a microbe,
`` to target it for
`` `` phagocytosis
substances that do this are opsonins - The major opsonins are
-
IgG antibodies
`` (acquired immunity),
complement protein
`` C3b,
mannose-binding lectin
C-reactive protein
last three are part of
`` `` innate immunity
`` all of which are recognized by
`` `` specific receptors on phagocytes - Receptors for opsonins
-
promote phagocytosis of opsonized microbes
`` and deliver signals that activate the phagocytes -
Phagocytosis
Engulfment -
Binding of a particle to phagocytic leukocyte receptors
`` initiates the process of
`` `` active phagocytosis of the particle
During engulfment,
`` extensions of the cytoplasm
`` `` (pseudopods)
`` flow around the particle to be engulfed,
`` eventually resulting in
`` `` complete enclosure of the particle within
`` a phagosome created by the plasma membrane of the cell
The membrane of phagosome then
`` fuses with the membrane of a lysosome,
`` resulting in discharge of the lysosomal contents
`` `` into the phagolysosome
The process of phagocytosis is complex
`` and is dependent
`` `` inter alia
`` on polymerization of
`` `` actin filaments
`` `` similar, to chemotactic process -
Phagocytosis
Killing and degradation -
The ultimate step in the elimination of
`` `` infectious agents and
`` `` necrotic cells
``is their
`` `` killing and
`` `` degradation
`` within activated
`` `` neutrophils and
`` `` macrophages -
Phagocytosis
Killing and degradation
Microbial killing is accomplished largely by -
oxygen-dependent mechanisms
Phagocytosis stimulates production of
`` reactive oxygen intermediates
`` `` ROIs, also called
`` `` reactive oxygen species - Oxygen dependent killing
-
The H2O2 generated by the NADPH oxidase system is
`` generally not able to efficiently kill microbes by itself
However, the azurophilic granules of neutrophils
`` contain the enzyme myeloperoxidase
`` `` (MPO),
`` which,
`` `` in the presence of a halide
`` `` `` such as Cl-,
`` converts H2O2 to hypochlorite
`` `` (HOCl),
`` which is a potent antimicrobial agent
`` that destroys microbes by halogenation
`` `` (in which the halide is bound covalently to cellular constituents)
`` or by oxidation of
`` `` `` proteins and
`` `` `` lipids
`` ``(lipid peroxidation)
The H2O2-MPO-halide system is
`` the most efficient bactericidal system in
`` `` neutrophils
MPO-deficient leukocytes are
`` capable of killing bacteria
`` `` (although more slowly than normal cells),
`` by formation of
`` `` superoxide (O2ָ)
`` `` and hydroxyl radicals
`` `` `` (OH⬢)
In addition, reactive nitrogen intermediates
`` `` e.g. nitric oxide (NO)
`` `` `` which also helps to kill microbes
`` `` are generated - Oxygen-independent killing 6
-
Various substances in leukocyte lysosomal granules
`` have antimicrobial activity
Bactericidal permeability increasing protein
`` ``(BPI)
`` causes increased permeability in the outer membrane of the microorganisms
Lysozyme hydrolyzes the muramic acid-N-acetyl-glucosamine bond in
`` the glycopeptide coat of
`` `` all bacteria
Eosinophilic major basic protein
`` has limited bactericidal activity
`` but is cytotoxic to many parasites
Defensins,
`` `` small cationic peptides,
``are cytotoxic to microbes
`` `` (and certain mammalian cells
Lactoferrin suppresses bacterial growth by
`` binding and sequestrating iron
Enzymes
`` `` elastase,
`` `` collagenase
`` in leukocytic granules contribute to
`` `` microbial killing. -
Phagocytosis
After microbial killing, -
lysosomal acid proteases
`` degrade the microbes within phagolysosomes
After phagocytosis,
`` neutrophils rapidly undergo
`` `` apoptosis
`` and are ingested by macrophages -
Leukocyte-induced tissue injury
If persistent and unchecked -
leukocyte infiltrate itself becomes
`` the offender,
`` and leukocyte-dependent tissue injury
`` `` underlies many
`` `` `` acute and
`` `` chronic diseases
During activation and phagocytosis,
`` leukocytes release microbicidal and other products
`` `` not only within the phagolysosome but also
`` `` into the extracellular space
Release of lysosomal contents may occur:
``if the lysosome releases its substances into
`` `` the transiently open phagosome
`` `` regurgitation during feeding
``if leukocytes are exposed to potentially ingestible materials,
`` `` such as immune complexes deposited on immovable flat surfaces
`` `` glomerular basement membrane
`` attachment of leukocytes to the immune complexes triggers
`` ``leukocyte activation,
`` `` ``but the fixed immune complexes cannot be phagocytosed,
`` `` `` and lysosomal enzymes are released into the medium
`` frustrated phagocytosis - The most important lysosomal substances that cause tissue injury are: 2
-
Lysosomal enzymes
Reactive oxygen intermediates: -
Tissue Injury
Lysosomal enzymes: -
Neutral proteases are capable of
`` degrading various extracellular components
`` `` collagen,
`` `` basement membrane,
`` `` fibrin,
`` `` elastin,
`` `` cartilage
`` resulting in the tissue destruction that
`` `` accompanies inflammatory processes
These harmful proteases, however, are held in check by
`` antiproteases in
`` `` the serum and
`` `` tissue fluids
`` `` `` α1-antitrypsin,
`` `` `` α2-macroglobulin -
Tissue Injury
Reactive oxygen intermediates: -
Oxygen-derived free radicals may be released extracellularly from
`` activated leukocytes
Extracellular release of low levels of these potent mediators can
`` increase the expression of chemokines
`` `` `` IL-8
`` `` cytokines, and
`` `` endothelial leukocyte adhesion molecules,
`` amplifying the cascade that
`` elicits the inflammatory response
At higher levels, release of these potent mediators can
`` be damaging to the host -
Tissue Injury
Oxygen-derived free radicals
Are implicated in the following processes: 3 -
Endothelial cell damage with
`` increased vascular permeability
Inactivation of antiproteases
`` `` (α1-antitrypsin)
``This leads to unopposed protease activity,
`` `` with increased destruction of extracellular matrix
Injury to other cell types
`` `` parenchymal cells,
`` `` red blood cells
`` Serum,
`` tissue fluids,
`` and host cells possess various antioxidants
`` `` superoxide dismutase,
`` `` catalase,
`` `` glutathione peroxidase,
`` `` ceruloplasmin,
`` `` transferrin
`` that protect the host against these potentially harmful oxygen-derived radicals - CHEMICAL MEDIATORS OF INFLAMMATION
-
Many inflammatory mediators have been identified,
`` and how they function in a coordinated manner is still not fully understood
Once activated and released from the cell,
`` most of these mediators are
`` ``short-lived
They quickly decay
`` `` arachidonic acid metabolites
`` or are inactivated by enzymes
`` `` kininase inactivates bradykinin
`` or they are otherwise scavenged
`` `` antioxidants scavenge toxic oxygen metabolites
`` or inhibited
`` `` complement regulatory proteins
`` `` `` break up and
`` `` `` degrade
`` `` `` `` activated complement components
There is thus a system of
`` checks and balances
`` in the regulation of mediator actions,
`` because most mediators have the potential to
`` `` cause harmful effects
A relatively small number of current drugs target
`` certain inflammatory mediators
`` `` or groups of mediators - Plasma-derived mediators
-
Plasma-derived mediators
`` `` kinins,
`` `` complement and
`` `` coagulation proteins
`` are present in plasma in precursor forms that
`` `` must be activated,
`` `` usually by a series of proteolytic cleavages,
`` to acquire their biologic properties -
Complement system
The complement system consists of -
proteins
`` `` (and their cleavage products)
`` produced by
`` `` liver
`` and secreted into plasma
This system functions in both
`` `` innate and
`` `` adaptive
`` immunity for defense against microbial agents -
Complement system
In the process of complement activation 4 -
a number of complement components are elaborated
`` that cause
`` `` increased vascular permeability,
`` `` chemotaxis,
`` `` opsonization, and
`` `` lysis of cells -
Complement System
Complement proteins are present as -
inactive forms in
`` plasma and
`` are numbered C1 through C9 -
Complement System
Many of these proteins are activated to become -
proteolytic enzymes that
`` degrade other complement proteins,
`` `` thus forming a cascade capable of
`` `` `` tremendous enzymatic amplification -
Complement System
The critical step in the elaboration of the biologic functions of complement is -
the activation of the third
`` `` (and most abundant) `` component,
`` `` C3 -
Complement System
Cleavage of C3 can occur by one of three pathways: -
the classical pathway,
`` which is triggered by
`` `` fixation of C1 to
`` `` `` antibody
`` `` `` `` IgM
`` `` `` `` IgG
`` combined with antigen;
the alternative pathway,
`` which can be triggered by
`` `` microbial surface molecules
`` `` `` endotoxin, or
`` `` `` LPS
`` in the absence of antibody;
the lectin pathway,
`` in which plasma mannose-binding lectin binds to
`` `` carbohydrates on microbes
`` and directly activates C1. -
Complement System
Whichever pathway is involved
in the early steps of complement activation,
they all lead to -
the formation of an active enzyme
`` `` called the C3 convertase,
`` which splits C3 into two functionally distinct fragments,
`` `` C3a and
`` `` C3b
C3a is released
`` and C3b becomes covalently attached to
`` `` the cell or molecule where
`` `` `` complement is being activated
C3b then binds to the
`` previously generated fragments to form
`` `` C5 convertase,
`` `` `` which cleaves C5 to
`` `` `` `` release C5a
The remaining C5b binds
`` the late components
`` `` C6-C9
`` culminating in the formation of
`` `` the membrane attack complex
`` `` `` MAC,
`` `` `` `` composed of multiple C9 molecules -
Complement System
The biologic functions of the complement system
fall into four general categories: -
Vascular phenomena:
`` C3a and C5a components stimulate
`` `` histamine release from mast cells
`` and thereby increase
`` `` vascular permeability and
`` `` cause vasodilation
`` They are called anaphylatoxins because
`` `` they have effects similar to those of
`` `` `` mast cell mediators that are involved in the reaction called anaphylaxis
Chemotaxis:
`` C5a is a powerful chemotactic agent for
`` `` neutrophils,
`` `` monocytes,
`` `` eosinophils, and
`` `` basophils
Phagocytosis:
`` C3b, when fixed to the bacterial cell wall,
`` `` act as opsonins and
`` `` favor phagocytosis by
`` `` `` neutrophils and
`` `` `` macrophages,
`` which bear cell surface receptors for these complement fragments
Cell lysis:
`` MAC
`` `` (polymerized C9)
`` forms a channel in lipid membranes which
`` `` allows fluid and ions to enter and
`` `` `` causes cell lysis -
Complement System
The activation of complement is -
tightly controlled by regulatory proteins
`` These proteins are generally absent from microbes;
`` accordingly, complement is activated by and functions against microorganisms
The presence of these inhibitors in host cell membranes
`` protects the host from inappropriate damage during
`` `` protective reactions against patholgens
These regulatory mechanisms include:
`` Regulation of C3 and C5 Convertases
`` C1 inhibitor
`` MAC formation inhibition -
Complement System
Regulation of C3 and C5 convertases -
Since the formation of C3 convertase
`` and the generation of C3b are
`` `` the central features of all complement pathways,
`` it is not surprising that many of the regulatory proteins are
`` `` directed at controlling these activities
These regulators function by
`` enhancing the dissociation
`` ``` (decay acceleration)
`` of the convertase complex
`` `` decay-accelerating factor [DAF]
`` or by
`` `` proteolytically cleaving C3b
`` `` factor I -
Complement System
Activation of C1 -
by an immune complex is
`` blocked by C1 inhibitor -
Complement System
Excessive complement activation is also prevented by -
a number of proteins that act to
`` inhibit MAC formation
`` `` CD59,
`` `` `` also called membrane inhibitor of reactive lysis -
Kinin system
Activation of the kinin system results in -
the release of the vasoactive bradykinin
Bradykinin causes
`` `` dilation of blood vessels,
`` `` increased vascular permeability
`` `` and pain
`` when injected into the skin
These effects are similar to those of
`` histamine
The cascade that eventually produces kinins is triggered
`` by activation of
`` `` Hageman factor
`` `` `` factor XII of the intrinsic clotting pathway
`` upon contact with negatively charged surfaces
`` `` LPS,
`` `` collagen
Acitvated factor XII
`` `` (XIIa = prekallikrein activator)
`` converts plasma prekallikrein into
`` `` kallikrein,
`` `` `` which cleaves high-molecular-weight kininogen,
`` to produce bradykinin
Kallikrein itself is a potent activator of
`` `` Hageman factor,
`` allowing for autocatalytic amplification of
`` `` the initial stimulus -
Clotting system and Inflamation
The clotting system and inflammation are -
intimately connected processes
The clotting system is divided into
`` two pathways that
`` `` converge,
`` culminating in the activation of
`` `` thrombin and
`` `` `` the formation of fibrin -
Clotting system and Inflammation
The intrinsic clotting pathway is -
a series of plasma proteins that
`` can be activated by Hageman factor
`` `` (factor XII),
`` a protein synthesized by
`` `` the liver
`` that circulates in an inactive form until
`` `` it encounters negatively charged surfaces
`` `` `` LPS,
`` `` `` collagen,
`` `` `` activated platelets -
Clotting system and Inflammation
Activated factor XII activates four mediator systems: -
Kinin system,
`` which produces vasoactive bradykinin
Clotting system,
`` which induces formation of thrombin and fibrin
`` Thrombin provides
`` `` the main link between the coagulation system and
`` `` inflammation
`` It induces mobilization of
`` `` P-selectin,
`` `` production of chemokines, and
`` `` expression of endothelial adhesion molecules;
`` `` induction of cyclooxygenase-2;
`` `` and production of nitric oxide
Fibrinolytic system,
`` which produces
`` `` plasmin and
`` `` degrades the fibrin
Complement system,
`` which produces anaphylatoxins
`` `` (C3a) -
Clotting System and Inflammation
Acute inflammation, by activating or damaging the endothelium, can -
trigger coagulation
`` and induce thrombus formation -
Clotting System and Inflammation
Conversely, the coagulation cascade induces -
inflammation,
`` primarily via
`` `` the actions of thrombin -
Cell-derived mediators
Cell-derived mediators are normally -
sequestered in intracellular granules that
`` need to be secreted
`` `` histamine in mast cell granules
`` or are synthesized de novo
`` `` prostaglandins,
`` `` cytokines
`` in response to a stimulus -
Cell-derived mediators
The major cellular sources -
are
`` `` platelets,
`` `` neutrophils,
`` `` monocytes-macrophages,
`` `` and mast cells,
`` but mesenchymal cells
`` `` endothelium,
`` `` smooth muscle,
`` `` fibroblasts
`` and most epithelia
`` can also be induced to
`` `` elaborate some of the mediators -
Vasoactive Amines
Histamine -
Preformed histamine is
`` present in granules of mast cell
It is also found in
`` `` blood basophils and
`` `` platelets
Since it is preformed and stored in granules,
`` histamine is among the
`` `` first mediators to be released during
`` `` `` inflammation -
Vasoactive Amines
Histamine is released by -
mast cell degranulation in response to
`` a variety of stimuli:
physical injury such as
`` `` trauma,
`` `` cold, or
`` `` heat
immune reactions involving
`` binding of antibodies to mast cells
fragments of complement called
`` anaphylatoxins
`` `` C3a and
`` `` C5a
cytokines
`` `` IL-1,
`` `` IL-8 -
Vasoactive Amines
Histamine causes -
dilation of the arterioles
`` and increases the permeability of venules -
Vasoactive Amines
Histamine is considered to be -
the principal mediator of
`` the immediate transient phase of
`` `` increased vascular permeability,
`` `` causing endothelial gaps -
Vasoactive Amines
Serotonin is a -
preformed vasoactive mediator
`` with actions similar to those of histamine
It is present in
`` `` platelets and
`` `` in mast cells of
`` rodents
`` `` but not humans - Arachidonic acid metabolites
-
When cells are activated by diverse stimuli,
`` their membrane lipids are rapidly remodeled to
`` generate biologically active lipid mediators
`` that serve as
`` `` intracellular or
`` `` extracellular
`` signals to affect a variety of biologic processes,
`` `` including
`` `` inflammation and
`` `` hemostasis -
Arachidonic acid metabolites
Arachidonic acid (AA) is released from -
membrane phospholipids
`` through the action of
`` `` cellular phospholipase
`` `` `` A2,
`` `` which is activated by
`` `` `` mechanical,
`` `` `` chemical, and
`` `` `` physical stimuli
`` `` or by other mediators
`` `` `` C5a -
Arachidonic acid metabolites
AA metabolites,
also called eicosanoids,
are -
synthesized by two major classes of enzymes:
cyclooxygenases
`` `` prostaglandins and
`` `` thromboxanes
lipoxygenases
`` `` leukotrienes and
`` `` lipoxins -
Arachidonic acid metabolites
Eicosanoids bind to -
many cell types
`` and can mediate
`` `` virtually every step of
`` `` `` inflammation -
Anti-inflammatory therapy
can be directed at many targets along the
eicosanoid biosynthetic pathways: 3 -
Cyclooxygenase Inhibitors
Lipooxygenase Inhibitors
Glucocorticoids - Cyclooxygenase inhibitors include 3
-
aspirin and other
`` nonsteroidal anti-inflammatory drugs
`` `` NSAIDs
Aspirin irreversibly inhibits
`` `` cyclooxygenase
`` by acetylation
COX-2 inhibitors are a newer class of these drugs
The finding that COX-2
`` is inducibly expressed only
`` `` in response to inflammatory stimuli
`` was the impetus for developing
`` `` antagonists against this enzyme to
`` `` `` reduce inflammation without
`` `` `` `` interfering with the physiologic functions of
`` `` `` `` `` AA metabolites mediated by COX-1
`` `` `` `` `` `` fluid and electrolyte balance in the kidneys,
`` `` `` `` `` `` cytoprotection in the gastrointestinal tract - Lipoxygenase inhibitors:
-
5-lipoxygenase
`` is not affected by NSAIDs,
`` and many new inhibitors of this enzyme pathway
`` `` have been developed for human medicine
Pharmacologic agents that
`` inhibit leukotriene production
`` or block leukotriene receptors
`` have been found useful
`` `` in the treatment of asthma - Broad-spectrum Inflammation inhibitors include
-
glucocorticoids
These powerful anti-inflammatory agents
`` may act by
`` `` down-regulating the expression of specific target genes,
`` `` `` including the genes encoding
`` `` `` `` COX-2,
`` `` `` ` phospholipase A2,
`` `` `` `` proinflammatory cytokines
`` `` `` `` `` such as IL-1 and
`` `` `` `` `` TNF
`` `` `` `` and nitric oxide synthase
`` `` `` `` `` iNOS
Glucocorticoids also
`` up-regulate genes that encode
`` `` potent anti-inflammatory proteins,
`` `` `` such as lipocortin 1
Lipocortin 1 inhibits release of
`` AA from membrane phospholipids -
Cytokines
Cytokines are -
proteins produced by
`` many cell types
`` `` principally activated
`` `` `` lymphocytes and
`` `` `` macrophages,
`` `` but also
`` `` `` endothelium,
`` `` `` epithelium, and
`` `` `` connective tissue cells
`` that modulate the functions of
`` `` other cell types -
Cytokines
TNF and IL-1 are two of the -
major cytokines that
`` mediate inflammation
They are produced mainly by
`` macrophages
`` `` activated by
`` `` `` endotoxin (LPS),
`` `` `` immune complexes,
`` `` `` physical injury,
`` `` `` and a variety of inflammatory stimuli -
Cytokines
TNF and IL-1
Their most important actions in inflammation are -
their effects on
`` `` endothelium,
`` `` leukocytes, and
`` `` fibroblasts
induction of systemic acute-phase reactions. -
TNF and IL-1
In endothelium, 3 -
they induce the synthesis of
`` endothelial adhesion molecules
`` and chemical mediators,
`` `` including other
`` `` `` cytokines,
`` `` `` chemokines,
`` `` `` eicosanoids, and
`` `` `` nitric oxide (NO
they increases the surface thrombogenicity
`` of the endothelium. -
TNF and IL-1
They induce secretion of -
cytokines by
`` leukocytes
TNF also induces priming of
`` neutrophils,
leading to augmented responses of these cells
`` to other mediators. -
TNF and IL-1
They induce 3 -
fibroblastic proliferation,
collagen synthesis
production of proteases -
TNF and IL-1
as well as IL-6
induce the systemic -
acute-phase responses
`` associated with
`` `` infection or
`` `` injury -
Chemokines
Chemokines are a family of 3 -
small
`` `` (8 to 10 kD)
`` cytokines that act
`` `` primarily as chemoattractants
`` `` `` for specific types of leukocytes
IL-8 is secreted predominantly by
`` `` activated macrophages and
`` `` endothelial cells
`` and causes
`` `` activation and
`` `` chemotaxis
`` of neutrophils,
`` with limited activity on
`` `` monocytes and
`` `` eosinophils
Macrophage inflammatory protein-1α
`` `` (MIP-1α)
`` generally attracts
`` `` monocytes,
`` `` eosinophils,
`` `` basophils, and
`` `` lymphocytes
`` but not neutrophils
Eotaxin selectively recruits
`` eosinophils - Nitric oxide (NO) 7
-
Inducible nitric oxide synthase
`` `` (iNOS)
`` is induced when
`` `` macrophages and
`` `` other cells
`` are activated by
`` `` cytokines
`` `` `` TNF
NO causes
`` vasodilation by
`` `` relaxing vascular smooth muscle
NO free radicals are toxic to
`` `` microbial and
`` `` mammalian cells
In addition, NO reduces
`` platelet aggregation and
`` adhesion,
`` inhibits several features of
`` mast cell-induced inflammation,
`` and serves as an
`` `` endogenous regulator of
`` `` `` leukocyte recruitment
Blocking NO production under normal conditions
`` promotes leukocyte
`` `` rolling and
`` `` adhesion
`` in postcapillary venules
delivery of exogenous NO
`` `` reduces leukocyte recruitment
Thus, production of NO is an
`` endogenous compensatory mechanism that
`` `` reduces inflammatory responses - mediators of acute inflammation 11
-
Histamine and serotonin
Bradykinin
C3a
C5a
Prostaglandins
Leukotriene
`` B4
Leukotriene
`` C4,
`` D4,
`` E4
Oxygen metabolites
IL-1 and TNF
Chemokines
Nitric oxyde -
Histamine and serotonin
Source
Vascular leakage
Chemotaxis
Other -
Mast cells,
platelets
+
- -
Bradykinin
Source
Vascular leakage
Chemotaxis
Other -
Plasma substrate
+
-
Pain -
C3a
Source
Vascular leakage
Chemotaxis
Other -
Plasma protein via liver
+
-
Opsonic fragment (C3b) -
C5a
Source
Vascular leakage
Chemotaxis
Other -
Plasma protein via liver
+
+
Leukocyte adhesion, activation -
Prostaglandins
Source
Vascular leakage
Chemotaxis
Other -
Mast cells, from membrane phospholipids
Potentiate other mediators
-
Vasodilation, pain, fever -
Leukotriene B4
Source
Vascular leakage
Chemotaxis
Other -
Leukocytes
-
+
Leukocyte adhesion, activation -
Leukotriene C4, D4, E4
Source
Vascular leakage
Chemotaxis
Other -
Leukocytes, mast cells
+
-
Bronchoconstriction, vasoconstriction -
Oxygen metabolites
Source
Vascular leakage
Chemotaxis
Other -
Leukocytes
+
-
Endothelial damage, tissue damage -
IL-1 and TNF
Source
Vascular leakage
Chemotaxis
Other -
Macrophages, other
-
+
Acute-phase reactions, endothelial activation -
Chemokines
Source
Vascular leakage
Chemotaxis
Other -
Leukocytes, others
-
+
Leukocyte activation -
Nitric oxyde
Source
Vascular leakage
Chemotaxis
Other -
Macrophages, endothelium
+
+
Vasodilation, cytotoxicity -
OUTCOMES OF ACUTE INFLAMMATION
3 -
Complete Resolution
Healing by connective tissue replacement
`` fibrosis
Progression of tissue response to chronic inflammantion -
OUTCOMES OF ACUTE INFLAMMATION
Complete resolution -
Complete resolution is the outcome when
`` the injury is limited
`` and the damaged parenchymal cells can
`` `` regenerate
Resolution involves
`` `` neutralization or
`` `` spontaneous decay of
`` the chemical mediators,
`` return of normal vascular permeability,
`` cessation of leukocytic infiltration,
`` apoptosis of neutrophils,
`` and finally removal of
`` `` edema fluid and
`` `` proteins,
`` `` leukocytes,
`` `` foreign agents, and
`` `` necrotic debris
`` from the site
Phagocytes and lymphatics play
`` a major role in these events -
OUTCOMES OF ACUTE INFLAMMATION
Healing by connective tissue replacement (fibrosis) -
This occurs after
`` `` substantial tissue destruction,
`` `` when the inflammatory injury involves
`` `` `` tissues that are incapable of regeneration,
`` `` or when there is abundant
`` `` `` necrotic tissue or
`` `` fibrin exudation
When the fibrinous exudate in
`` `` tissue or
`` `` serous cavities
`` `` `` pleura,
`` `` `` peritoneum
`` cannot be adequately cleared,
`` granulation tissue grows into the area of exudate,
`` converting it into a mass of fibrous tissue
`` a process also called
`` `` organization
In many pyogenic infections
`` there may be intense
`` `` neutrophil infiltration and
`` `` liquefaction of tissues,
`` `` leading to pus formation
The destroyed tissue is
`` resorbed
`` and eventually replaced by
`` `` fibrosis -
OUTCOMES OF ACUTE INFLAMMATION
Progression of the tissue response to chronic inflammation -
This may
`` follow acute inflammation,
`` or the response may be chronic
`` `` almost from the onset
Acute to chronic transition occurs
`` when the acute inflammatory response
`` ` cannot be resolved
`` owing either to
`` `` the persistence of the injurious agent
`` `` or to some interference with the normal process of healing
For example,
`` bacterial infection of the lung
`` `` may begin as a focus of acute inflammation
`` `` `` pneumonia
`` but its failure to resolve may
`` `` lead to extensive tissue destruction
`` `` and formation of a cavity
`` `` `` in which the inflammation continues to smolder,
`` `` `` leading eventually to a chronic lung abscess - SUMMARY OF ACUTE INFLAMMATION
-
When a host encounters for example a pathogen,
`` phagocytes that reside in all tissues
`` `` try to get rid of these agents
At the same time,
`` `` phagocytes,
`` `` mast cells
`` `` and other host cells
`` react to the presence of the “foreigner†by
`` `` liberating
`` `` `` cytokines,
`` `` `` lipid messengers,
`` `` and the various other mediators of inflammation
Histamine and others act on the adjacent vasculature
`` `` inducing arteriolar
dilation,
`` `` increased blood flow and
`` `` opening of capillary beds
`` `` `` (redness = rubor; warmth = calor)
`` in the injured area
Increased vascular permeability results in
`` the accumulation of protein-rich extravascular fluid
`` `` (edemaïƒ swelling = tumor)
`` `` `` Immediate and transient
`` `` `` `` histamine, etc
`` `` ``` and delayed
`` `` `` `` IL-1, TNF
`` vascular permeability
Plasma proteins
`` leave the vessels,
`` `` most commonly through widened interendothelial cell junctions
`` `` `` (gaps)
Circulating leukocytes,
`` `` initially predominantly neutrophils,
`` adhere to the endothelium
`` `` margination,
`` `` rolling,
`` `` firm adhesion
`` via adhesion molecules
`` transmigrate across the endothelium
`` and migrate to the site of injury
`` under the influence of chemotactic agents
`` `` (chemotaxis)
Leukocytes that are activated
`` try to remove the offending agent by
`` `` phagocytosis
During phagocytosis,
`` `` toxic metabolites and
`` `` proteases
`` may be released extracellularly
`` and cause tissue damage
As the injurious agent is eliminated,
`` the inflammatory process disappears
`` and the host returns to a normal state of health
If the injurious agent cannot be quickly eliminated,
`` the result may be chronic inflammation -
CHRONIC INFLAMMATION
Chronic inflammation is considered to be -
inflammation of prolonged duration
`` `` (weeks or months)
`` in which
`` `` active inflammation,
`` `` tissue destruction,
`` `` and attempts at repair
`` are proceeding simultaneously -
CHRONIC INFLAMMATION
Chronic inflammation may -
follow acute inflammation
or it begins as low-grade subclinical process
`` progressing to clinically apparent chronic inflammatory diseases
`` with tissue damage and fibrosis (
`` `` sarcoptic mange,
`` `` rheumatoid arthritis,
`` `` atherosclerosis,
`` `` tuberculosis,
`` `` chronic lung diseases -
Chronic Inflammation
Morphologic features -
In contrast to acute inflammation,
`` which is manifested by
`` `` vascular changes,
`` `` edema,
`` `` fibrin, and
`` `` predominantly neutrophilic infiltration,
`` chronic inflammation is characterized by:
Mononuclear infiltration
`` consisting of
`` `` macrophages,
`` `` lymphocytes,
`` `` and plasma cells
Tissue destruction
`` induced by
`` `` the persistent offending agent
`` `` or by the inflammation -
Tissue repair:
Morphologic features -
proliferation of
`` small blood vessels
`` `` (angiogenesis)
and fibrosis -
Macrophage
The macrophage is the - dominant cellular player in chronic inflammation
-
Macrophage
Macrophages originate from -
blood monocytes
and from tissue macrophages
`` liver
`` `` (Kupffer cells),
`` spleen and
`` lymph nodes
`` `` (sinus histiocytes),
`` and lungs (
`` `` alveolar macrophages)]
Blood monocytes
`` migrate into various tissues
`` `` and differentiate into macrophages -
Macrophage
The half-life of -
blood monocytes is about
`` 1 day,
whereas the life span of tissue macrophages is
`` several months
`` or years -
Macrophage
Monocytes begin to emigrate -
into extravascular tissues
`` quite early
`` `` in acute inflammation,
`` and within
`` `` 48 hours
`` they may constitute the predominant cell type -
Macrophage
When the monocyte reaches the extravascular tissue -
it undergoes transformation
`` into a larger phagocytic cell
`` `` the macrophage -
Macrophage
In short-lived inflammation -
if the irritant is eliminated,
`` macrophages eventually disappear
`` `` either dying off or
`` `` making their way into
`` `` `` the lymphatics and
`` `` `` lymph nodes -
Macrophage
In chronic inflammation - macrophage accumulation persists
-
Macrophage
Macrophages are powerful host “defenders†3 -
using an impressive arsenal of “weaponsâ€:
Lysosomal
`` `` oxygen-dependent and
`` `` oxygen-independent
`` toxic products
Secretion of
`` `` cytokines and
`` `` chemokines
`` causing influx of inflammatory cells
Secretion of
`` `` growth factors
`` causing
`` `` angiogenesis and
`` `` fibrosis
These products of activated macrophages serve to
`` eliminate injurious agents
`` and to initiate the process of repair of damaged tissue - Lymphocytes are mobilized
-
in both
`` `` antibody-mediated and
`` `` cell-mediated
`` immune reactions. - Lymphocytes and macrophages interact in a
-
bidirectional way,
and these reactions play an important role in
`` chronic inflammation
Macrophages present antigens to
`` `` T cells
`` and produce cytokines
`` `` IL-12
`` that stimulate
`` `` T-cell responses - Activated T lymphocytes produce
-
cytokines
`` `` (IFN-γ)
`` that stimulate macrophages - Plasma cells develop
-
from activated B lymphocytes
`` and produce antibody directed
`` `` either against persistent antigen in
`` `` `` the inflammatory site
`` `` or against
`` `` `` altered tissue components - Lympho-plasmacytic inflammation has
-
little diagnostic specificity,
`` because almost all inflammatory diseases will,
`` `` sooner or later,
`` become dominated by
`` `` long-lived mononuclear cells -
Granulomatous inflammation
Granulomatous inflammation is -
a distinctive pattern of
`` chronic inflammatory reaction characterized by
`` `` focal accumulations of
`` `` `` activated macrophages,
`` `` which often develop an
`` `` `` epithelioid appearance -
Granulomatous inflammation
A granuloma is -
a focus of
`` chronic inflammation
`` `` consisting of an
`` `` `` aggregation of epithelioid macrophages
`` `` `` often with giant cells
`` `` `` surrounded by
`` `` `` `` lymphocytes,
`` `` `` `` occasionally plasma cells
`` `` `` and intermingling fibroblasts -
Granulomatous inflammation
pyogranulomatous -
Depending on the causative agent,
`` some granulomas may contain
`` `` substantial amounts of neutrophils
`` `` forming
`` `` `` purulent exudate
therefore, such processes is called pyogranulomatous -
Granulomatous inflammation
The macroscopic appearance of a granuloma is often -
indistinguishable from a neoplasm,
`` because it is usually
`` `` a nodular
`` `` grey-white
`` `` mass -
Granulomatous inflammation
Microscopically, granulomatous inflammation should always -
be examined with special stains to
`` identify potential causative agents
In veterinary medicine,
`` `` foreign body,
`` `` fungal, and
`` `` mycobacterial
`` granulomas are most common -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Homeostasis -
Homeostatic mechanisms are designated to
`` maintain an optimal internal environment in
`` the face of a constantly changing external environment
During a particularly strong challenge to this homeostasis
`` an acute phase response might
`` `` take priority over this internal optimal balance
`` `` `` in order to defend the host from
`` `` `` `` a potentially life-threatening homeostatic disturbance -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
The acute phase response is -
an adaptive component of
`` innate defence
`` and consists of numerous
`` `` predetermined and
`` `` well-orchestrated
`` `` `` local and
`` `` `` systemic
`` `` physiological reactions to
`` the acute phase stimuli -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Is mediated predominantly by
the following three cytokines: -
IL-1,
TNF
IL-6 -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
The acute phase response consists of 5 -
several
`` clinical and
`` pathologic changes:
fever,
anorexia,
somnolence,
acute phase proteins,
leukocytosis
etc -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Fever
Fever is -
one of the most prominent manifestations of
`` the acute phase response,
`` especially when
`` `` inflammation is associated
`` `` `` with infection -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Fever
Fever is produced in response -
to substances called
`` pyrogens
`` `` exogenous
`` `` `` (LPS)
`` ``endogenous
`` ``` `` IL-1,
`` `` `` TNF
`` that induce production of
`` `` prostaglandins
`` `` `` (especially PGE2)
`` `` from arachidonic acid by
`` `` `` cyclooxygenases in
`` `` `` the vascular and
`` `` `` perivascular cells
`` `` of the
`` `` `` hypothalamus -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Fever
PGE2 stimulates production of -
neurotransmitters
`` `` (cyclic AMP),
`` which function to reset
`` `` the temperature set-point at
`` `` `` a higher level -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Fever
An elevated body temperature -
has been shown to help amphibians
`` to fight off microbial infections,
``and it is assumed that
`` fever does the same
`` `` for mammals,
`` `` `` although the mechanism is unknown -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Fever
One hypothesis is that fever -
may induce
`` `` heat shock proteins
`` that enhance
`` `` lymphocyte responses to
`` `` `` microbial antigens -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE Proteins
Acute phase proteins are -
proteins produced by
`` `` the liver
`` whose plasma concentrations are
`` `` altered by
`` `` `` 25% or more
`` `` during the acute phase response
Positive acute phase proteins
`` `` increase
`` and
`` negative acute phase proteins
`` `` decrease
`` in concentration during
`` `` the acute phase response -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE Proteins
Most of the positive acute phase proteins have -
important host protective
`` `` anti-inflammatory or
`` `` antimicrobial functions,
whereas
`` the function of
`` `` negative acute phase proteins is
`` associated with
`` `` maintenance of homeostasis -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE Proteins
Reactivity of acute phase proteins - varies tremendously among species
-
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE Proteins
classification based on their function or structure: 4 -
Opsonins:
`` C-reactive protein,
`` serum amyloid A,
`` mannose binding lectin
Proteinase inhibitors:
`` `` alpha2 macroglobulin
`` They regulate
`` `` complement,
`` `` coagulation and
`` `` fibrinolytic cascades
`` and inactivate
`` `` proteinases
`` `` `` released from leukocytes
Metal binding proteins:
`` transferrin
`` `` (binds iron),
`` haptoglobin
`` `` (binds hemoglobin),
`` ceruloplasmin
`` `` (binds copper)
`` Iron and copper are
`` `` essential elements of
`` `` `` numerous enzymes and
`` `` `` metabolic mechanisms
`` for
`` `` many prokaryotic and
`` `` all eukaryotic
`` organisms
`` Vertebrates have
`` `` various
`` `` `` metal binding proteins and
`` `` `` mechanisms to prevent cation mediated toxicity
`` `` `` and to sequestrate microelements from
`` `` `` `` invading pathogens
Coagulation and complement proteins:
`` fibrinogen,
`` C3,
`` C4 -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE Proteins
Clinical importance: -
concentration of fibrinogen is
`` used to determine if
`` `` ruminants and
`` `` horses
`` are in acute phase response
The other acute phase proteins are
`` not commonly used in veterinary medicine
`` `` presently,
`` `` but they will be in the near future
Acute phase proteins are common diagnostic tools used in human medicine - Leukocytosis is a common
-
feature of inflammatory reactions,
`` especially those
`` `` induced by bacterial infection -
SYSTEMIC EFFECTS OF INFLAMMATION
Leukocytosis
leukocytosis occurs initially -
because of
`` accelerated release of
`` `` cells from the
`` `` `` bone marrow
`` `` `` `` postmitotic reserve pool
`` `` caused by
`` `` `` IL-1 and
`` `` `` TNF
therefore leukocytosis is associated with
`` a rise in the number of
`` `` more immature neutrophils
`` `` `` in the blood
`` `` `` `` (shift to the left -
SYSTEMIC EFFECTS OF INFLAMMATION
Leukocytosis
Prolonged infection -
also induces
`` proliferation of precursors
`` `` in the bone marrow,
thus, the bone marrow output
`` of leukocytes is
`` `` increased to compensate for
`` `` `` the loss of these cells
`` `` `` `` in the inflammatory reaction -
SYSTEMIC EFFECTS OF INFLAMMATION
ACUTE PHASE RESPONSE
Other manifestations 4 -
Rigors
`` (shivering),
chills
`` (search for warmth),
anorexia
somnolence
probably because of
`` the actions of cytokines
`` `` on brain -
SHOCK
Shock is -
(cardiovascular collapse)
a circulatory
`` `` dyshomeostasis
`` associated with
`` `` loss of circulating blood volume,
`` `` reduced cardiac output,
`` `` and/or inappropriate peripheral vascular resistance
Hypotension results in
`` impaired tissue perfusion and
`` cellular hypoxia
`` and a shift to anaerobic metabolism by cells,
`` cellular degeneration,
`` and death -
SHOCK
Shock is rapidly progressive and life threatening -
when
`` compensatory responses are
`` `` inadequate -
Shock
Cardiogenic shock results from -
failure of the heart to
`` adequately pump blood
`` `` which leads to
`` `` `` stagnation of blood and
`` `` `` progressive tissue hypoperfusion -
Shock
Hypovolemic shock arises from -
reduced circulating blood volume
`` due to blood loss caused by
`` `` hemorrhage,
`` or due to fluid loss
`` `` secondary to
`` `` `` vomiting,
`` `` `` diarrhea, or
`` `` `` burns
Reduced circulating blood volume leads to
`` decreased vascular pressure and
`` tissue hypoperfusion -
Shock
Hypovolemic shock
Immediate compensatory mechanisms 2 act -
peripheral vasoconstriction
fluid movement into the plasma
act to
`` increase vascular pressure
`` and maintain blood flow to
`` `` critical tissues, such as the
`` `` heart,
`` `` brain, and
`` `` kidney -
Shock
Blood maldistribution
is characterized by -
decreased peripheral vascular resistance
pooling of blood in peripheral tissues
Systemic vasodilation results in
`` a dramatically increased
`` `` microvascular area,
`` and although the blood volume is normal,
`` `` the effective circulating blood volume is
`` `` `` decreased -
Shock
The three major types of shock
due to blood maldistribution are -
anaphylactic,
neurogenic,
septic shock -
Shock
Anaphylactic shock is - a generalized type I hypersensitivity
-
Shock
Anaphylactic shock
Common causes 3 -
exposure to
`` insects,
`` plants,
`` or drugs -
Shock
Anaphylactic shock
Mechanism -
The interaction of
`` `` the inciting allergen with
`` `` immunoglobulin E
`` `` `` bound to mast cells
`` results in
`` `` widespread mast cell degranulation
`` `` and the release of
`` `` `` histamine and
`` `` `` other vasoactive mediators
Subsequently,
`` there is
`` `` systemic vasodilation and
`` `` increased vascular permeability,
`` causing
`` `` hypotension and
`` `` tissue hypoperfusion -
Shock
Neurogenic shock
4 Ways and the Means -
may be induced by
`` trauma,
`` electrocution,
`` lightning,
`` emotional stress
The autonomic nervous system induces
`` `` peripheral vasodilation,
`` `` followed by
`` `` `` tissue hypoperfusion -
Septic Shock
Septic shock is -
the most common type of shock
`` associated with blood maldistribution -
Shock
Septic shock
In septic shock -
peripheral vasodilation is
`` caused by the release of
`` `` excessive amounts of
`` `` `` vascular and
`` `` `` inflammatory
`` `` mediators
`` induced by
`` `` bacterial components
`` `` `` endotoxin (LPS)
`` `` `` `` gram-negative
`` `` `` or peptidoglycans
`` `` `` and lipoteichoic acids
`` `` `` `` gram-positive -
Shock
Septic shock
Local release of LPS
Where and 4 Effects -
from degenerating bacteria
`` is a potent stimulus for
`` `` many of the host responses that are
`` `` `` necessary for defense against bacteria
LPS activates:
monocytes/macrophages
`` which release
`` `` TNF,
`` `` IL-l and
`` `` IL-6
endothelium
`` which decrease production of
`` `` anticoagulant substances
factor XII
`` to initiate
`` `` intrinsic coagulation
`` `` and other pathways
`` `` `` kinins,
`` `` `` fibrinolysis,
`` `` `` complement
directly alternative complement pathway
These events are important for enhancing
`` the inflammatory response
`` `` to control
`` `` `` localized infections associated with
`` `` `` `` relatively low concentrations of LPS
However, they can be
`` `` detrimental
`` if the response becomes
`` `` more pronounced due to
`` `` `` overwhelming bacterial infections
`` `` `` `` generating large concentrations of LPS
`` `` `` `` which induces increased production of
`` `` `` `` `` TNF,
`` `` `` `` `` IL-l and
`` `` `` `` `` other cytokines -
Shock
Septic shock
If cytokine activation cascade is not controlled
1 Consequence
6 Actions -
septic shock will follow
TNF and/or IL-l are
`` central mediators of septic shock
They:
induce
`` tissue factor expression
`` and endothelial activation of
`` `` extrinsic coagulation
enhance expression of
`` endothelial leukocyte adhesion molecules
mediate delayed endothelial leakage
stimulate arachidonic acid metabolite production
induce nitric oxide production
`` (vasodilation)
activate neutrophils
`` and enhance their adhesion to
`` endothelium,
`` `` which further interferes with
`` `` `` blood flow through the microvasculature
The end result of the activation of these myriad
`` `` vascular,
`` `` proinflammatory, and
`` `` procoagulant alterations
`` is the profound systemic
`` `` vasodilation,
`` `` hypotension, and
`` `` tissue hypoperfusion -
Shock
Septic shock
Morphologic changes: 5 -
Septicemic animals may have any combination of the following changes:
Congested
`` `` skin and
`` `` peripheral organs,
`` due to
`` `` vasodilation
petechiation
`` `` Serosal,
`` `` mucosal and/or
`` `` parenchymal
`` due to
`` `` endothelial damage and
`` `` DIC
Diffuse
`` `` pulmonary edema and
`` `` congestion
`` due to
`` `` endothelial leakage and
`` `` vasodilation
Mild
`` `` fibrinous polyserositis and
`` `` polyarthritis
`` due to
`` `` endothelial leakage/damage
Enlarged
`` `` spleen and
`` `` lymph nodes
`` due to
`` `` activation of residual tissue macrophages - Bacteremia –
- presence of bacteria in the blood
- Septicemia –
-
presence of bacteria in the blood
`` that cause systemic disease - Endotoxemia –
-
presence of endotoxin (LPS) in the blood
`` that causes systemic disease -
Stages and progression of shock
3 -
Regardless of the underlying cause,
`` shock generally progresses through
`` `` three different stages
Nonprogressive Stage
Progressive Stage
Irreversible Stage -
Shock
Nonprogressive stage is characterized by
3 and outcome -
the following compensatory mechanisms
`` that counteract
`` `` reduced functional circulating blood volume
`` `` and decreased vascular pressure:
epinephrine/norepinephrine
`` increases cardiac output
`` and causes arteriolar vasoconstriction
`` `` (increased peripheral resistance)
`` in most tissues
`` `` (except vital organs)
`` in an attempt to
`` `` raise vascular pressure;
ADH and renin-angiotensin system
`` `` (aldosterone)
`` increase plasma volume
`` `` water retention,
`` `` sodium retention,
`` `` vasoconstriction
decreased microvascular pressure
`` results in a shift in
`` `` fluid movement from
`` `` `` the interstitium into
`` `` `` `` the plasma
`` to also help increase
`` `` blood volume
This compensation results in
`` `` increased heart rate,
`` `` cardiac output, and
`` `` vascular pressure -
Shock
Progressive stage
5 and Outcome -
follows if compensatory mechanisms are inadequate
Cellular metabolism becomes
`` less efficient
`` and shifts from
`` `` aerobic to
`` `` anaerobic with
`` `` `` pyruvate converted to
`` `` `` `` lactate without entering the Krebs cycle
The deficient production of ATP
`` and overproduction of lactic acid
`` inhibits
`` `` normal cell functions
`` `` `` and results in
`` `` `` `` cellular and
`` `` `` `` systemic
`` `` `` `` `` acidosis
Local
`` `` hypoxia and
`` `` accumulation of metabolic products
`` eventually result in
`` `` arteriolar
`` `` `` relaxation and
`` `` ` dilation
Once these local influences
`` `` override
`` `` `` centrally mediated vasoconstriction
`` `` `` `` widespread peripheral vasodilation
`` `` `` `` `` decreases vascular pressure even more
`` and it is unlikely that
`` `` shock will be reversed
Oxygen and energy stores of the cell are
`` depleted and
`` `` cell necrosis occurs -
Shock
Irreversible stage is generally assured -
when shock progresses into
`` the syndrome of multiple organ dysfunction
Vicious cycles occur in which
`` the failing function of one organ
`` `` contributes to the failure of another
e.g., decreased cardiac output causes
`` renal ischemia;
`` `` electrolyte imbalances caused by renal ischemia then
`` `` `` result in cardiac arrhythmias